PACIFIC-9: Phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer.

Evidence from the Phase III PACIFIC trial established durvalumab, a monoclonal antibody (mAb) targeting PD-L1, following concurrent chemoradiotherapy (cCRT) as a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). There remains an unmet need to improve upon the outcomes achieved with the PACIFIC regimen. Combining durvalumab with other immunotherapies may improve outcomes further. Two such immunotherapies include oleclumab, an mAb targeting CD73, and monalizumab, an mAb targeting NKG2A. Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT.Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov).

Durvalumab is a treatment that helps the body's immune system to identify and attack cancer cells by binding to a protein called PD-L1. Studies show that durvalumab lowers the risk of cancer growing or spreading, and prolongs survival, when administered after chemotherapy and radiation therapy ('chemoradiotherapy') in patients with a type of lung cancer called stage III non-small-cell lung cancer (NSCLC) for whom surgery is not an option.Two antibody treatments have been developed that may help a patient's immune system to identify and attack cancer cells. Oleclumab binds to a protein on cancer cells called CD73, which prevents the production of adenosine, a chemical that obstructs the immune system from attacking the cancer. Monalizumab binds to NKG2A, a protein on immune cells that inhibits their ability to destroy cancer cells. Early studies suggest that combining either of these treatments with durvalumab may be better than durvalumab alone for slowing the growth and spread of cancer in patients with NSCLC.PACIFIC-9 is a study that aims to recruit approximately 999 patients with stage III NSCLC for whom surgery is not an option and who have completed chemoradiotherapy without the cancer growing or spreading. Patients will be randomly assigned in equal numbers to receive up to a year of treatment with durvalumab plus oleclumab, durvalumab plus monalizumab or durvalumab plus placebo. The primary measure of efficacy is the length of time that patients remain alive without the cancer growing or spreading for each combination versus durvalumab plus placebo.

Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer.

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.

Impact of pembrolizumab treatment duration on overall survival and prognostic factors in advanced non-small cell lung cancer: a nationwide retrospective cohort study.

Background: The efficacy of front-line pembrolizumab has been established in studies that limit treatment duration to 2 years, but decision to stop pembrolizumab after 2 years is often at physician's discretion. ATHENA is a retrospective cohort study using a comprehensive administrative database aimed firstly at exploring the optimal duration of pembrolizumab and secondly real-life prognosis factors in patients with advanced non-small cell lung cancer (NSCLC). Methods: Using the French National Health Insurance database (SNDS), we identified patients with incident lung cancer in France from 2015 to 2022. Treatments and patients' characteristics were extracted or inferred from hospital, outpatient care, pharmacy delivery reports. The duration's hazard ratio (HR) was estimated with Cox model weighted by inverse of propensity score to account for confounding. Prognostics factors in first line population were identified with Cox model selected by a LASSO procedure. Findings: 391,106 patients with lung cancer were identified, of whom 43,359 received up-front pembrolizumab for an advanced disease. There were 67% (29,040/43,359) of male and the median age at diagnosis was 65 years old. After a median follow-up time of 25.9 months (min-max, [0-97.6]), the median overall survival (OS) after pembrolizumab initiation in first line was 15.7 [CI 95, 15.3-16.0] months. In multivariable analysis, several covariables were independently associated with worse OS, including male sex with chemo-immunotherapy, age, hospital category, high deprivation index, inpatient hospitalization for first pembrolizumab, and history of diabetes, diuretic, beta blocker, painkiller prescription. At landmark time of 29 months after pembrolizumab initiation, continuation beyond 2 years was not associated with better OS than a fixed 2-year treatment, HR = 0.97 [0.75-1.26] p = 0.95. Interpretation: This study supports the notion that stopping pembrolizumab after 2 years could be safe for patients with advanced NSCLC. However, because observational studies are prone to confounding and selection bias, causality cannot be affirmed. Funding: This study did not receive any specific grant.

Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review.

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.

Long-Term Outcomes After Concurrent Once- or Twice-Daily Chemoradiation in Limited-Stage Small Cell Lung Cancer: A Brief Report From the CONVERT Trial.

PURPOSE: CONVERT was a phase 3 international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5-year outcomes of these regimens delivered with conformal techniques. METHODS AND MATERIALS: CONVERT (NCT00433563) randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks), both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance. RESULTS: Five hundred forty-seven patients were recruited at 73 centers. The median follow-up for the surviving cohort (n = 164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95% CI, 21.1-30.9) and 30.0 months (95% CI, 25.3-36.5; hazard ratio, 1.13; 95% CI, 0.92-1.38; P = .247). Performance status and tumor volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms, respectively. CONCLUSIONS: As the CONVERT trial did not demonstrate the superiority of OD RT and this regimen had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer.

Overcoming immuno-resistance by rescheduling anti-VEGF/cytotoxics/anti-PD-1 combination in lung cancer model.

Background: Many tumors are refractory to immune checkpoint inhibitors, but their combination with cytotoxics is expected to improve sensitivity. Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors. Methods: In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model. A longitudinal immunomonitoring study on tumor, spleen, and blood after multiple treatments including Cisplatin, Pemetrexed, and anti-VEGF, either alone or in combination, was performed, spanning a period of up to 21 days, to determine the optimal time window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence), as well as single agent anti-PD1. Results: Immunomonitoring showed marked differences between treatments, organs, and time points. However, harnessing tumor immunity (i.e., promoting CD8 T cells or increasing the T CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a 14-day delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities (i.e., -71% in tumor volume compared to control). Conclusions: Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1.

Real-World Treatment Patterns and Clinical Outcomes After Platinum-Doublet Chemotherapy and Immunotherapy in Metastatic Non-Small Cell Lung Cancer: A Multiregional Chart Review in the United States, Europe, and Japan.

PURPOSE: To characterize treatment patterns and real-world clinical outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) who developed progression on an anti-PD-1/anti-PD-L1, herein referred to as anti-PD-(L)1, and platinum-doublet chemotherapy. METHODS: Eligible oncologists/pulmonologists in the United States, Europe (France, Germany, and United Kingdom), and Japan completed electronic case report forms for patients with mNSCLC (no evidence of EGFR/ALK/ROS1 alterations). Eligible patients had disease progression on/after an anti-PD-(L)1 and platinum-doublet chemotherapy (received concurrently or sequentially), initiated a subsequent line of therapy (LOT) between 2017 and 2021, and had an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 at this subsequent LOT initiation (index date). Overall survival (OS), time to treatment discontinuation (TTD), and real-world progression-free survival (rwPFS) after index were assessed using Kaplan-Meier analysis. RESULTS: Overall, 160 physicians (academic, 54.4%; community, 45.6%) provided deidentified data from 487 patient charts (United States, 141; Europe, 218; Japan, 128; at mNSCLC diagnosis: median age 66 years, 64.7% male, 81.3% nonsquamous, 86.2% de novo mNSCLC; at line of interest initiation: 86.0% ECOG 0-1, 39.6% liver metastases, 18.9% brain metastases, 79.1% smoking history). The most common treatment regimens upon progression after anti-PD-(L)1/platinum-doublet chemotherapy were nonplatinum chemotherapy (50.5%), nonplatinum chemotherapy plus vascular endothelial growth factor receptor inhibitor (12.9%), and platinum-doublet chemotherapy (6.6%). Median OS was 8.8 months (squamous, 7.8 months; nonsquamous, 9.5 months). Median TTD was 4.3 months (squamous, 4.1 months; nonsquamous, 4.3 months). Median rwPFS was 5.1 months (squamous, 4.6 months; nonsquamous, 5.4 months). CONCLUSION: In this multiregional, real-world analysis of pooled patient chart data, patients with mNSCLC who had disease progression after anti-PD-(L)1/platinum-doublet chemotherapy had poor clinical outcomes with various treatment regimens, demonstrating an unmet clinical need for effective options after failure on anti-PD-(L)1 and platinum-doublet chemotherapy treatments.

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial.

BACKGROUND: STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). PATIENTS AND METHODS: Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. RESULTS: Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1-3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2-4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5-10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6-5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. CONCLUSION: This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

Meta-Analysis on the Combination of Chemotherapy With Programmed Death-Ligand 1 and Programmed Cell Death Protein 1 Blockade as First-Line Treatment for Unresectable Pleural Mesothelioma.

INTRODUCTION: Dual immune checkpoint blockers regimen represents a standard first-line therapy in unresectable pleural mesothelioma (PM). Novel combination strategies, including immune checkpoint blockers and antiangiogenic drugs, are currently under investigation in this setting. We aimed to assess the efficacy of the chemoimmunotherapy combination by reference to literature evidence. METHODS: A systematic review and meta-analysis of trials with first-line platinum-based chemotherapy associated with programmed death-ligand 1 and programmed cell death protein 1 agent in unresectable PM. We estimated the weighted summary proportion of disease response, along with the landmark probability of survival outcomes. RESULTS: A total of 349 patients with unresectable PM from four trials (DREAM, PrE0505, JME-001, and IND.227) were included, 79% (n = 274) with epithelioid and 21% (n = 75) with nonepithelioid histologic type. In aggregate, the objective response rate was 59.2% (95% confidence interval [CI]: 50.3%-67.9%) and disease control rate was 92.2% (95% CI: 89.2%-94.8%). Comparing epithelioid versus nonepithelioid tumors, the objective response rate was 64.5% versus 46.4%, (p < 0.001) and the disease control rate was 92.3% versus 80.0%, (p = 0.043), with an OR of 2.56 (95% CI: 1.51-4.32) for disease response and of 3.37 (95% CI: 0.99-11.47) for disease control. The aggregated estimated probability of progression-free survival was 63% (95% CI: 53%-71%) at 6 months and 25% (95% CI: 21%-31%) at 12 months, whereas the 6-, 12- and 24-month overall survival rates were 88% (95% CI: 81%-93%), 71% (95% CI: 61%-79%) and 39% (95% CI: 34%-45%), respectively. CONCLUSIONS: According to our analysis, first-line chemoimmunotherapy holds promise as a new treatment approach for PM, exhibiting encouraging survival outcomes and an enhanced response rate, including for the epithelioid subtype. Ongoing studies are necessary to establish its precise placement within the treatment algorithm.

TROP2 Is Associated with Primary Resistance to Immune Checkpoint Inhibition in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest the involvement of trophoblast cell surface antigen 2 (TROP2) in modulating tumor cell resistance to therapeutic drugs, its specific role in the context of PD-1/PD-L1 axis blockade is not definitively established. EXPERIMENTAL DESIGN: We performed high-throughput analysis of transcriptomic data from 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy in two large randomized clinical trials. To confirm our results at the protein level, we complemented this transcriptional approach by performing a multiplex immunofluorescence analysis of tumor tissue samples as well as a proteomic profiling of plasma. RESULTS: We observed a significant association of TROP2 overexpression with worse progression-free survival and overall survival on PD-L1 blockade, independent of other prognostic factors. Importantly, we found increased TROP2 expression to be predictive of survival in patients treated with atezolizumab but not chemotherapy. TROP2 overexpression was associated with decreased T-cell infiltration. We confirmed these results at the proteomic level both on tumor tissue and in plasma. CONCLUSIONS: Our results suggest an important contribution of TROP2 expression to the primary resistance to PD-L1 blockade in NSCLC. TROP2-biomarker-based strategy may be relevant in selecting patients with NSCLC who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent.

Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non-Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial.

PURPOSE: Effective treatments for resectable non-small-cell lung cancer (NSCLC) are limited and relapse rates are high. The interleukin (IL)-1ß pathway has been linked with tumor development and progression, including in the Canakinumab Anti-Inflammatory Thrombosis Outcomes cardiovascular study in which IL-1ß pathway inhibition with canakinumab reduced lung cancer incidence and mortality in an exploratory analysis. METHODS: CANOPY-A (ClinicalTrials.gov identifier: NCT03447769) is a phase III, randomized, double-blind, multicenter study of canakinumab versus placebo for adult patients with stage II-IIIA or IIIB (T >5 cm, N2-positives II-IIIB; American Joint Committee on Cancer/Union for International Cancer Control version 8), completely resected NSCLC who had received adjuvant cisplatin-based chemotherapy. The primary end point was disease-free survival (DFS) and the key secondary end point was overall survival (OS). RESULTS: In total, 1,382 patients were randomized to 200 mg canakinumab (n = 693) or placebo (n = 689) once every 3 weeks for 18 cycles. Grade ≥3 adverse events (AEs) were reported in 20.8% and 19.6% of patients receiving canakinumab and placebo, respectively; AEs led to discontinuation in 4.3% and 4.1% of patients in these groups, respectively. This study did not meet its primary end point. Median DFS was 35.0 months (canakinumab arm) and 29.7 months (placebo arm; hazard ratio, 0.94; 95% CI, 0.78 to 1.14; one-sided P = .258). DFS subgroup analyses did not show any meaningful differences between arms. As expected, because of canakinumab-driven IL-1ß pathway inhibition, C-reactive protein and IL-6 levels decreased in the canakinumab arm versus placebo arm, but had no correlation with differential clinical outcomes. OS was not formally tested as DFS was not statistically significant. CONCLUSION: CANOPY-A did not show a DFS benefit of adding canakinumab after surgery and adjuvant cisplatin-based chemotherapy in patients with resected, stage II-III NSCLC. No new safety signals were identified with canakinumab.

Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study.

INTRODUCTION: Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment. METHODS: This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. On the basis of the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary end point). RESULTS: A total of 153 patients were randomized to either BA (n = 75) or durvalumab groups (n = 78). The median progression-free survival was 12.8 months versus 14.6 months (stratified hazard ratio = 1.48 [95% confidence interval: 0.69-3.17]), in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% versus 32.1%) and disease control rate (66.7% versus 70.5%) were similar between the two groups. Any-grade treatment-emergent adverse events occurred in 94.6% versus 96.1% of patients in the BA versus durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). CONCLUSIONS: BA with cCRT followed by BA exhibited no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial.

INTRODUCTION: We report the primary analysis from JAVELIN Lung 100, a phase 3 trial comparing avelumab (anti⁠-programmed death-ligand 1 [PD-L1]) versus platinum-based doublet chemotherapy as first-line treatment for PD-L1-positive (+) advanced NSCLC. METHODS: Adults with PD-L1+ (≥1% of tumor cells; PD-L1 immunohistochemistry 73-10 pharmDx), EGFR and ALK wild-type, previously untreated, stage IV NSCLC were randomized to avelumab 10 mg/kg every 2 weeks (Q2W), avelumab 10 mg/kg once weekly (QW) for 12 weeks and Q2W thereafter, or platinum-based doublet chemotherapy every 3 weeks. Primary end points were overall survival (OS) and progression-free survival (PFS) per independent review committee. The primary analysis population was patients with high-expression PD-L1+ tumors (≥80% of tumor cells). RESULTS: A total of 1214 patients were randomized to avelumab Q2W (n = 366), avelumab QW (n = 322), or chemotherapy (n = 526). In the primary analysis population, hazard ratios (HRs) for OS and PFS with avelumab Q2W (n = 151) versus chemotherapy (n = 216) were 0.85 (95% confidence interval [CI]: 0.67-1.09; one-sided p = 0.1032; median OS, 20.1 versus 14.9 mo) and 0.71 (95% CI: 0.54-0.93; one-sided p = 0.0070; median PFS, 8.4 versus 5.6 mo), respectively. With avelumab QW (n = 130) versus chemotherapy (n = 129), HRs were 0.79 (95% CI: 0.59-1.07; one-sided p = 0.0630; median OS, 19.3 versus 15.3 mo) and 0.72 (95% CI: 0.52-0.98; one-sided p = 0.0196; median PFS, 7.5 versus 5.6 mo), respectively. No new safety signals were observed. CONCLUSIONS: Longer median OS and PFS were observed with avelumab versus platinum-based doublet chemotherapy in advanced NSCLC, but differences in OS and PFS were not statistically significant, and the trial did not meet its primary objective. CLINICALTRIALS: gov Identifier: NCT02576574.

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.